Musculoskeletal System - Cartilage Development

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Endochondral bone


The musculoskeletal system consists of skeletal muscle, bone, and cartilage and is mainly mesoderm in origin with some neural crest contribution.

Fetal head (week 12)

The mesoderm forms nearly all the connective tissues of the musculoskeletal system. Each tissue (cartilage, bone, and muscle) goes through many different mechanisms of differentiation. Recent studies[1] show that Sox9 acts as a key regulator of early chondrocyte differentiation.

The intraembryonic mesoderm can be broken into paraxial, intermediate and lateral mesoderm relative to its midline position. During the 3rd week the paraxial mesoderm forms into "balls" of mesoderm paired either side of the neural groove, called somites. Somites appear bilaterally as pairs at the same time and form earliest at the cranial (rostral,brain) end of the neural groove and add sequentially at the caudal end. This addition occurs so regularly that embryos are staged according to the number of somites that are present. Different regions of the somite differentiate into dermomyotome (dermal and muscle component) and sclerotome (forms vertebral column). An example of a specialized musculoskeletal structure can be seen in the development of the limbs.

Skeletal muscle forms by fusion of mononucleated myoblasts to form mutinucleated myotubes. Bone is formed through a lengthy process involving ossification of a cartilage formed from mesenchyme. Two main forms of ossification occur in different bones, intramembranous (eg skull) and endochondrial (eg limb long bones) ossification. Ossification continues postnatally, through puberty until mid 20s. Early ossification occurs at the ends of long bones.

Musculoskeletal and limb abnormalities are one of the largest groups of congenital abnormalities.

Musculoskeletal Links: Introduction | Mesoderm | Somitogenesis | Limb | Cartilage | Bone | Bone Timeline | Axial Skeleton | Skull | Joint | Muscle | Muscle Timeline | Tendon | Diaphragm | Lecture - Musculoskeletal Development | Lecture Movie | Abnormalities | Limb Abnormalities | Cartilage Histology | Bone Histology | Skeletal Muscle Histology | Category:Musculoskeletal
Historic Musculoskeletal Embryology  
1902 - Pubo-femoral Region | Spinal Column and Back | Body Segmentation | Cranium | Body Wall, Ribs, and Sternum | Limbs | 1901 - Limbs | 1902 - Arm Development | 1906 Human Embryo Ossification | 1906 Lower limb Nerves and Muscle | 1907 - Muscular System | Skeleton and Limbs | 1908 Vertebra | 1909 Mandible | 1910 - Skeleton and Connective Tissues | Muscular System | Coelom and Diaphragm | 1913 Clavicle | 1920 Clavicle | 1921 - External body form | Connective tissues and skeletal | Muscular | Diaphragm | 1929 Rat Somite | 1932 Pelvis | 1940 Synovial Joints | 1943 Human Embryonic, Fetal and Circumnatal Skeleton | 1947 Joints | 1949 Cartilage and Bone | 1957 Chondrification Hands and Feet | 1968 Knee

Some Recent Findings

  • Long-term expandable SOX9+ chondrogenic ectomesenchymal cells from human pluripotent stem cells[1] "Here we report the successful generation and long-term expansion of SOX9-expressing CD271(+)PDGFRα(+)CD73(+) chondrogenic ectomesenchymal cells from the PAX3/SOX10/FOXD3-expressing MIXL1(-)CD271(hi)PDGFRα(lo)CD73(-) neural crest-like progeny of human pluripotent stem cells in a chemically defined medium supplemented with Nodal/Activin/transforming growth factorβ (TGFβ) inhibitor and fibroblast growth factor (FGF). When "primed" with TGFβ, such cells efficiently formed translucent cartilage particles, which were completely mineralized in 12 weeks in immunocompromized mice." Developmental Signals - Sox
  • Fibroblast growth factor and canonical WNT/β-catenin signaling cooperate in suppression of chondrocyte differentiation in experimental models of FGFR signaling in cartilage[2]Aberrant fibroblast growth factor (FGF) signaling disturbs chondrocyte differentiation in skeletal dysplasia, but the mechanisms underlying this process remain unclear. Recently, FGF was found to activate canonical WNT/β-catenin pathway in chondrocytes via Erk MAP kinase-mediated phosphorylation of WNT co-receptor Lrp6. Here, we explore the cellular consequences of such a signaling interaction. WNT enhanced the FGF-mediated suppression of chondrocyte differentiation in mouse limb bud micromass and limb organ cultures, leading to inhibition of cartilage nodule formation in micromass cultures, and suppression of growth in cultured limbs. Simultaneous activation of the FGF and WNT/β-catenin pathways resulted in loss of chondrocyte extracellular matrix, expression of genes typical for mineralized tissues and alteration of cellular shape. WNT enhanced the FGF-mediated downregulation of chondrocyte proteoglycan and collagen extracellular matrix via inhibition of matrix synthesis and induction of proteinases involved in matrix degradation. Expression of genes regulating RhoA GTPase pathway was induced by FGF in cooperation with WNT, and inhibition of the RhoA signaling rescued the FGF/WNT-mediated changes in chondrocyte cellular shape. Our results suggest that aberrant FGF signaling cooperates with WNT/β-catenin in suppression of chondrocyte differentiation."
  • Review - Current understanding on the molecular basis of chondrogenesis[3] "Endochondral bone formation involves multiple steps, consisting of the condensation of undifferentiated mesenchymal cells, proliferation and hypertrophic differentiation of chondrocytes, and then mineralization. To date, various factors including transcription factors, soluble mediators, extracellular matrices (ECMs), and cell-cell and cell-matrix interactions have been identified to regulate this sequential, complex process. Moreover, recent studies have revealed that epigenetic and microRNA-mediated mechanisms also play roles in chondrogenesis. Defects in the regulators for the development of growth plate cartilage often cause skeletal dysplasias and growth failure."
More recent papers  
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  • Therefore the list of references do not reflect any editorial selection of material based on content or relevance.
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References listed on the rest of the content page and the associated discussion page (listed under the publication year sub-headings) do include some editorial selection based upon both relevance and availability.

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Search term: Cartilage Embryology

Nandar Mya, Toshiko Furutera, Shigeru Okuhara, Tsutomu Kume, Masaki Takechi, Sachiko Iseki Transcription factor Foxc1 is involved in anterior part of cranial base formation. Congenit Anom (Kyoto): 2018; PubMed 29322554

Miki Shimbo, Riku Suzuki, Sayaka Fuseya, Takashi Sato, Katsue Kiyohara, Kozue Hagiwara, Risa Okada, Hiromasa Wakui, Yuki Tsunakawa, Hideto Watanabe, Koji Kimata, Hisashi Narimatsu, Takashi Kudo, Satoru Takahashi Postnatal lethality and chondrodysplasia in mice lacking both chondroitin sulfate N-acetylgalactosaminyltransferase-1 and -2. PLoS ONE: 2017, 12(12);e0190333 PubMed 29287114

Evan J Propst Revision repair of type IV laryngotracheoesophageal cleft using multiple long tapered engaging grafts. Int. J. Pediatr. Otorhinolaryngol.: 2017, 103;80-82 PubMed 29224771

Bernadette S de Bakker, Henri M de Bakker, Vidija Soerdjbalie-Maikoe, Frederik G Dikkers The development of the human hyoid-larynx complex revisited. Laryngoscope: 2017; PubMed 29219191

Agata Białoszewska, Joanna Olkowska-Truchanowicz, Katarzyna Bocian, Anna Osiecka-Iwan, Andrzej Czop, Claudine Kieda, Jacek Malejczyk A Role of NKR-P1A (CD161) and Lectin-like Transcript 1 in Natural Cytotoxicity against Human Articular Chondrocytes. J. Immunol.: 2017; PubMed 29212911

Older papers  
  • SOX9 determines RUNX2 transactivity by directing intracellular degradation [4] "In analyses of the mechanism by which SOX9 regulated RUNX2 function, we demonstrated that SOX9 induced a dose-dependent degradation of RUNX2. ...Furthermore, SOX9 was able to decrease the level of ubiquitinated RUNX2 and direct RUNX2 to the lysosome for degradation. SOX9 also preferentially directed β-catenin, an intracellular mediator of canonical Wnt signaling, for lysosomal breakdown."
  • SOX9 is a major negative regulator of cartilage vascularization, bone marrow formation and endochondral ossification[5] "...SOX9 is able to directly suppress Vegfa expression by binding to SRY sites in the Vegfa gene. Postnatally, bone marrow formation and cartilage resorption in transgenic offspring are resumed by massive invasion of capillaries through the cortical bone shaft, similar to secondary ossification. These findings imply that downregulation of Sox9 in the hypertrophic zone of the normal growth plate is essential for allowing vascular invasion, bone marrow formation and endochondral ossification."


  • The Developing Human: Clinically Oriented Embryology (8th Edition) by Keith L. Moore and T.V.N Persaud - Moore & Persaud Chapter 15 the skeletal system
  • Larsen’s Human Embryology by GC. Schoenwolf, SB. Bleyl, PR. Brauer and PH. Francis-West - Chapter 11 Limb Dev (bone not well covered in this textbook)
  • Before we Are Born (5th ed.) Moore and Persaud Chapter 16,17: p379-397, 399-405
  • Essentials of Human Embryology Larson Chapter 11 p207-228


  • Identify the components of a somite and the adult derivatives of each component.
  • Give examples of sites of (a) endochondral and (b) intramembranous ossification and to compare these two processes.
  • Identify the general times (a) of formation of primary and (b) of formation of secondary ossification centres, and (c) of fusion of such centres with each other.
  • Briefly summarise the development of the limbs.
  • Describe the developmental abnormalities responsible for the following malformations: selected growth plate disorders; congenital dislocation of the hip; scoliosis; arthrogryposis; and limb reduction deformities.

Development Overview

Below is a very brief overview using simple figures of 3 aspects of early musculoskeletal development. More detailed overviews are shown on other notes pages Mesoderm and Somite, Vertebral Column, Limb in combination with serial sections and Carnegie images.

Mesoderm Development

Mesoderm cartoon 01.jpg Cells migrate through the primitive streak to form mesodermal layer. Extraembryonic mesoderm lies adjacent to the trilaminar embryo totally enclosing the amnion, yolk sac and forming the connecting stalk.
Mesoderm cartoon 02.jpg Paraxial mesoderm accumulates under the neural plate with thinner mesoderm laterally. This forms 2 thickened streaks running the length of the embryonic disc along the rostrocaudal axis. In humans, during the 3rd week, this mesoderm begins to segment. The neural plate folds to form a neural groove and folds.
Mesoderm cartoon 03.jpg Segmentation of the paraxial mesoderm into somites continues caudally at 1 somite/90minutes and a cavity (intraembryonic coelom) forms in the lateral plate mesoderm separating somatic and splanchnic mesoderm.

Note intraembryonic coelomic cavity communicates with extraembryonic coelom through portals (holes) initially on lateral margin of embryonic disc.

Mesoderm cartoon 04.jpg Somites continue to form. The neural groove fuses dorsally to form a tube at the level of the 4th somite and "zips up cranially and caudally and the neural crest migrates into the mesoderm.

Somite Development

Mesoderm cartoon 05.jpg Mesoderm beside the notochord (axial mesoderm, blue) thickens, forming the paraxial mesoderm as a pair of strips along the rostro-caudal axis.
Mesoderm cartoon 06.jpg Paraxial mesoderm towards the rostral end, begins to segment forming the first somite. Somites are then sequentially added caudally. The somitocoel, is a cavity forming in early somites, which is lost as the somite matures.
Mesoderm cartoon 07.jpg Cells in the somite differentiate medially to form the sclerotome (forms vertebral column) and dorsolaterally to form the dermomyotome.
Mesoderm cartoon 08.jpg The dermomyotome then forms the dermotome (forms dermis) and myotome (forms muscle).

Neural crest cells migrate beside and through somite.

Mesoderm cartoon 09.jpg The myotome differentiates to form 2 components dorsally the epimere and ventrally the hypomere, which in turn form epaxial and hypaxial muscles respectively. The bulk of the trunk and limb muscle coming from the Hypaxial mesoderm. Different structures will be contributed depending upon the somite level.

Limb Development

Mesoderm cartoon 09.jpg


  1. 1.0 1.1 Katsutsugu Umeda, Hirotsugu Oda, Qing Yan, Nadine Matthias, Jiangang Zhao, Brian R Davis, Naoki Nakayama Long-Term Expandable SOX9(+) Chondrogenic Ectomesenchymal Cells from Human Pluripotent Stem Cells. Stem Cell Reports: 2015; PubMed 25818812
  2. Marcela Buchtova, Veronika Oralova, Anie Aklian, Jan Masek, Iva Vesela, Zhufeng Ouyang, Tereza Obadalova, Zaneta Konecna, Tereza Spoustova, Tereza Pospisilova, Petr Matula, Miroslav Varecha, Lukas Balek, Iva Gudernova, Iva Jelinkova, Ivan Duran, Iveta Cervenkova, Shunichi Murakami, Alois Kozubik, Petr Dvorak, Vitezslav Bryja, Pavel Krejci Fibroblast growth factor and canonical WNT/β-catenin signaling cooperate in suppression of chondrocyte differentiation in experimental models of FGFR signaling in cartilage. Biochim. Biophys. Acta: 2015; PubMed 25558817
  3. Toshimi Michigami Current understanding on the molecular basis of chondrogenesis. Clin Pediatr Endocrinol: 2014, 23(1);1-8 PubMed 24532955 | Clin Pediatr Endocrinol.
  4. Aixin Cheng, Paul G Genever SOX9 determines RUNX2 transactivity by directing intracellular degradation. J. Bone Miner. Res.: 2010, 25(12);2680-9 PubMed 20593410
  5. Takako Hattori, Catharina Müller, Sonja Gebhard, Eva Bauer, Friederike Pausch, Britta Schlund, Michael R Bösl, Andreas Hess, Cordula Surmann-Schmitt, Helga von der Mark, Benoit de Crombrugghe, Klaus von der Mark SOX9 is a major negative regulator of cartilage vascularization, bone marrow formation and endochondral ossification. Development: 2010, 137(6);901-11 PubMed 20179096


Masaharu Takigawa CCN2: a master regulator of the genesis of bone and cartilage. J Cell Commun Signal: 2013, 7(3);191-201 PubMed 23794334

| MC3709051 | J Cell Commun Signal. Yasuhiko Kawakami, Joaquín Rodriguez-León, Juan Carlos Izpisúa Belmonte The role of TGFbetas and Sox9 during limb chondrogenesis. Curr. Opin. Cell Biol.: 2006, 18(6);723-9 PubMed 17049221

Mary B Goldring, Kaneyuki Tsuchimochi, Kosei Ijiri The control of chondrogenesis. J. Cell. Biochem.: 2006, 97(1);33-44 PubMed 16215986

Lillian Shum, Glen Nuckolls The life cycle of chondrocytes in the developing skeleton. Arthritis Res.: 2002, 4(2);94-106 PubMed 11879545


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